Impaired maturation and differentiation of oligodendrocytes in the vacuole formation myelin mutant rat

The vacuole formation (VF) rat is an autosomal recessive myelin mutant characterized by generalized tremor, hypomyelination, and periaxonal VF of the central nervous system. We previously identified a nonsense mutation in the <i>DOP1 leucine zipper-like protein A</i> (<i>Dop1a</i>, also known as <i>Dopey1</i>) gene located on rat chromosome 8. In this study, we investigated the kinetics of oligodendrocyte progenitor cells (OPCs) and oligodendrocytes by assessing the expression patterns of transcription factors that are involved in oligodendrocyte development. The number of small, round oligodendrocytes lacking distinct cellular processes, immunolabeled with anti-adenomatous polyposis coli (APC, clone CC1) antibody, was increased in the spinal cords of the VF rats, suggesting a disrupted maturation of oligodendrocytes. In addition, the terminal differentiation and maturation of OPCs into myelinating mature oligodendrocytes may be impaired and compensatory myelination largely could fail in the VF rat. Our findings also demonstrated that the DOP1A protein is expressed in OPCs as well as mature oligodendrocytes. Finally, the intracellular trafficking of <i>myelin basic protein</i> (<i>Mbp</i>) mRNAs may be disrupted in oligodendrocytes of the VF rats. Our data suggested that DOP1A dysfunction causes impaired differentiation and maturation of oligodendrocyte-lineage cells, resulting in hypomyelination and an impaired compensatory myelination.